Mounting evidence suggests that the long-term impact of traumatic brain injury (TBI) may be far worse than previously thought. A history of brain trauma increases an individual's risk of developing Alzheimer's disease (AD), and TBI can induce the rapid formation of amyloid-? (A?) plaques, a hallmark pathology of AD. Pioneering work from this grant has demonstrated that massive accumulations of amyloid precursor protein (APP) in damaged axons after TBI are accompanied by the very secretases that cleave APP to form A?. Uniquely, this anabolic process occurs within the axonal membrane compartment of humans with TBI and in animal models of TBI. However, although this axonal process persists for years after TBI, the frequency of A? plaques appears to diminish within months. This suggests that there is also a potential A? catabolic process after TBI. Indeed, we have shown in preliminary data using multiple models that neprilysin, the primary A? degrading enzyme, may have a key role in clearing A? following injury. In addition, preliminary human studies demonstrate stunning evidence that A? plaques reappear several years and even decades after TBI. From these collective data, we hypothesize that there is a long-term shifting balance between A? anabolism and catabolism after TBI. Remarkably, through preliminary examination we also found the other hallmark pathology of AD, neurofibrillary tangles (NFTs), in long-term survivors of TBI. This is further supported by the demonstration of NFTs chronically following injury in our unique swine model. This finding represents a significant new avenue in the exploration of mechanisms linking TBI and AD and is the first demonstration that NFT formation occurs chronically following just a single TBI. For this application, we propose a molecules-to-man approach to determine evolving mechanisms of AD-like pathologies after TBI. Through our longstanding collaboration between investigators at the University of Pennsylvania and Glasgow, UK, we will investigate long-term neuropathological changes after TBI, using the world's only comprehensive TBI human brain archive. In parallel interactive studies, we will examine well-characterized experimental models at the in vivo and in vitro level to determine the cellular and molecular mechanisms of A? plaque and NFT genesis. In addition, we will examine the effects of A? reduction after injury in experimental models with a view to therapeutic intervention. Success of these studies will provide insight into mechanisms that convert a single TBI into a progressive neurodegenerative disease.